S-adenosylmethionine as an epigenetic treatment of depression in adults with childhood trauma.

BACKGROUND

Childhood trauma is associated with increased risk of depression and epigenetic alterations in stress-related pathways. Preclinical studies suggest that methyl donors may facilitate DNA methylation changes. This first-in-human trial of epigenetic treatment investigated methyl donor S-adenosylmethionine (SAMe) as add-on to trauma-focused therapy for depression.

METHODS

In this randomized, double-blind, placebo-controlled trial with 6-month follow-up, 31 adults with trauma-related depression were enrolled. Participants received 1200 mg SAMe or placebo alongside 12-weeks trauma-focused therapy. Depression symptoms were assessed using the Hamilton Rating Scale of Depression (HAM-D). Plasma SAMe levels and genome-wide DNA methylation were measured pre- and post-treatment, including epigenome-wide association analyses, differentially methylated region analyses, and epigenetic clock measures.

RESULTS

Twenty-eight participants completed the study. Depression symptoms decreased significantly during treatment and remained improved at follow-up, reflecting the effect of psychotherapy, without clinical benefit of SAMe. SAMe supplementation did not alter plasma SAMe levels. However, SAMe treatment was associated with differential methylation across 66 regions. Epigenetic clock analyses showed no consistent treatment-related changes.

CONCLUSIONS

This first-in-human epigenetic intervention study in psychiatry demonstrates the feasibility of combining trauma-focused psychotherapy with targeted epigenetic analyses. While SAMe showed no additive clinical effects, the results provide important leads for future trials.

CLINICAL TRIAL IDENTIFIER (EUDRACT): 2017-002097-38.